Welsh 2010

Caffeine for asthma (Review)
Welsh EJ, Bara A, Barley E, Cates CJ
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 1
http://www.thecochranelibrary.com
Caffeine for asthma (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Analysis 1.1. Comparison 1 All caffeine doses versus placebo, Outcome 1 FEV1 outcomes at ’short’ time frame. . . 22
Analysis 1.2. Comparison 1 All caffeine doses versus placebo, Outcome 2 FEV1 outcomes at ’medium’ time frame. . 23
Analysis 1.3. Comparison 1 All caffeine doses versus placebo, Outcome 3 FEV1 outcomes at ’long’ time frame. . . 24
Analysis 1.4. Comparison 1 All caffeine doses versus placebo, Outcome 4 FEF 25-75 outcomes at ’short’ time frame. 25
Analysis 1.5. Comparison 1 All caffeine doses versus placebo, Outcome 5 FEF 25-75 outcomes at ’medium’ time frame. 26
Analysis 1.6. Comparison 1 All caffeine doses versus placebo, Outcome 6 FEF 25-75 outcomes at ’long’ time frame. 27
Analysis 1.7. Comparison 1 All caffeine doses versus placebo, Outcome 7 Gaw/VL outcomes at ’short’ time frame. . 28
Analysis 1.8. Comparison 1 All caffeine doses versus placebo, Outcome 8 FEV1 outcomes at 2 hours. . . . . . . 29
Analysis 1.9. Comparison 1 All caffeine doses versus placebo, Outcome 9 FEV1 outcomes at 2 hours (High dose). . 30
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 35
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Caffeine for asthma (Review) i

[Intervention Review]
Caffeine for asthma
Emma J Welsh1 , Anna Bara2 , Elizabeth Barley3 , Christopher J Cates1

1 Population
Health Sciences and Education, St George’s, University of London, London, UK. 2 Medical Research Unit, Clinical Trials
Unit, London, UK. 3 Florence Nightingale School of Nursing and Midwifery, King’s College London, London, UK
Contact address: Emma J Welsh, Population Health Sciences and Education, St George’s, University of London, Cranmer Terrace,
London, SW17 0RE, UK. ewelsh@sgul.ac.uk.
Editorial group: Cochrane Airways Group.

Publication status and date: Stable (no update expected for reasons given in ’What’s new’), published in Issue 8, 2012.
Review content assessed as up-to-date: 11 August 2011.
Citation: Welsh EJ, Bara A, Barley E, Cates CJ. Caffeine for asthma. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.:
CD001112. DOI: 10.1002/14651858.CD001112.pub2.
ABSTRACT
Background
Caffeine has a variety of pharmacological effects; it is a weak bronchodilator and it also reduces respiratory muscle fatigue. It is chemically
related to the drug theophylline which is used to treat asthma. It has been suggested that caffeine may reduce asthma symptoms and
interest has been expressed in its potential role as an asthma treatment. A number of studies have explored the effects of caffeine in
asthma; this is the first review to systematically examine and summarise the evidence.
Objectives
To assess the effects of caffeine on lung function and identify whether there is a need to control for caffeine consumption prior to either
lung function or exhaled nitric oxide testing.
Search methods
We searched the Cochrane Airways Group trials register and the reference lists of articles (August 2011), an updated search in June
2011 yielded one potentially relevant article which has been added to ’studies awaiting classification’. We also contacted study authors.
Selection criteria
We included randomised trials (RCTs) of oral caffeine compared to placebo or coffee compared to decaffeinated coffee in adults with
asthma.
Data collection and analysis
Two review authors independently carried out trial selection, quality assessment and data extraction.
Main results
We included seven trials involving a total of 75 people with mild to moderate asthma. The studies were all of cross-over design.
Six trials involving 55 people showed that in comparison with placebo, caffeine, even at a ’low dose’ (less than 5 mg/kg body weight),
appears to improve lung function for up to two hours after consumption. Forced expiratory volume in one second (FEV1) showed a
small improvement up to two hours after caffeine ingestion (standardised mean difference 0.72; 95% confidence interval 0.25 to 1.20),
which translates into a 5% mean difference in FEV1. However in two studies the mean differences in FEV1 were 12% and 18% after
caffeine. Mid-expiratory flow rates also showed a small improvement with caffeine and this was sustained up to four hours.
Caffeine for asthma (Review) 1
One trial involving 20 people examined the effect of drinking coffee versus a decaffeinated variety on the exhaled nitric oxide levels in
patients with asthma and concluded that there was no significant effect on this outcome.
Authors’ conclusions
Caffeine appears to improve airways function modestly, for up to four hours, in people with asthma. People may need to avoid caffeine
for at least four hours prior to lung function testing, as caffeine ingestion could cause misinterpretation of the results. Drinking
caffeinated coffee before taking exhaled nitric oxide measurements does not appear to affect the results of the test, but more studies are
needed to confirm this.
PLAIN LANGUAGE SUMMARY
The effect of caffeine in people with asthma
Caffeine is found in coffee, tea, cola drinks and cocoa. Caffeine is a drug that is very similar to theophylline. Theophylline is a
bronchodilator drug that is taken to open up the airways in the lungs and therefore relieve the symptoms of asthma, such as wheezing,
coughing and breathlessness. Scientists are interested in finding out whether caffeine has the same effect on the lungs as theophylline.
There are two major reasons why it is important to know if caffeine is a bronchodilator. The first is because it may be beneficial for
asthmatics to take caffeine in order to relieve the symptoms of asthma. The second is because consuming caffeine may affect the results
of important tests that determine how bad someone’s asthma is.
If caffeine acts as a bronchodilator and widens the airways, then a patient who has consumed caffeine before taking the test would show
a better result in a lung function test than they would have if they had not consumed any caffeine. The potential problem with this is
that if the test results are better than expected doctors may prescribe a lower dose or a weaker drug than is really necessary, which can
lead to problems with asthma management.
This review carefully examines all the available high-quality clinical trials on caffeine in asthma. This review was conducted to discover
if people should avoid consuming caffeine before taking lung function tests.
This review found that even small amounts of caffeine can improve lung function for up to four hours. Therefore caffeine can affect
the result of a lung function test (e.g. spirometry) and so caffeine should be avoided before taking a lung function test if possible, and
previous caffeine consumption should be recorded.
It is not known if taking caffeine leads to improvements in symptoms. It may be that in order to improve the symptoms of asthma,
caffeine is needed in such large amounts that the drug’s adverse effects would become a problem, so more research is needed.
Another clinical trial looked at the effect of caffeine on exhaled nitric oxide levels and found that there is no significant effect, so it
appears unlikely that patients would need to avoid caffeine before taking this type of test. However, this is the result of just a single
study so more research is needed to clarify this.
The general pharmacological effects of caffeine have been ex-

BACKGROUND tensively investigated and are described in several reviews (e.g.
Curatolo 1983; Stephenson 1977). Early studies reported that caf-
Caffeine has been widely consumed throughout the world for cen-
feine improved mental performance and increased motor activity
turies. It is used for both non-medical and medical purposes. It is
(Cheney 1935) and this has been confirmed in other studies. Caf-
ubiquitous, being found in coffee, tea, cola-flavoured soft drinks
feine ingestion has also been shown to elevate oxygen consumption
and compounds containing cocoa. Caffeine and its derivatives
(Grollman 1930), increase respiratory rates in disease-free patients
have therapeutic uses and are contained in medicines such as anal-
(Robertson 1978) and increase ventilation in patients with coro-
gesics and cold remedies.
nary obstructive pulmonary disease (COPD) (Woodcock 1981). METHODS
Caffeine belongs to a group of chemicals called methylxanthines,
along with the bronchodilator drug theophylline. As a class, these
drugs have a history of use in respiratory disorders. The mecha-
Criteria for considering studies for this review
nism of action of the methylxanthines is uncertain, but is possibly
due to their inhibition of the enzyme phosphodiesterase. Phospho-
diesterase hydrolyses cyclic adenosine monophosphate (cAMP)
which is a messenger within the cell that regulates many func- Types of studies
tions including the contraction and relaxation of smooth muscle.
Methylxanthines are also competitive antagonists for adenosine We included randomised trials (RCTs) only.
receptors. One of the effects of adenosine, a chemical regulator,
is that of bronchoconstriction. Methylxanthines are known to be
weak bronchodilators and they also interact with respiratory mus- Types of participants
cles to reduce respiratory muscle fatigue. Some believe the latter to
We included adults (older than 18 years) with previously docu-
be more important than the former in the treatment of respiratory
mented asthma of any level of severity.
diseases.
Thus, interest has been expressed in the potential role of caffeine
as a treatment in respiratory disease (Pagano 1988). As early as
Types of interventions
1859, Salter (in Becker 1984) recommended coffee as one of the
best remedies for asthma. A study of the general Italian population We included the following comparisons:
in 1983 by Pagano 1988 found an inverse relationship between 1. oral caffeine versus placebo; and
the prevalence of bronchial asthma and the amount of coffee con- 2. coffee versus decaffeinated coffee.
sumed. From this, the authors suggested that caffeine may reduce
asthma symptoms.
Types of outcome measures
We did not use outcome measures to decide if a study was eligible
Why it is important to do this review for inclusion in the review.
Despite the amount of information regarding caffeine and its po- We did not include challenge test data in this review.
tential effectiveness in obstructive airways diseases, no reviews have
been conducted that examine the evidence in a systematic fashion.
The results from such a review could have important implications
Primary outcomes
for research and clinical practice.
1. Lung function outcomes used were: forced expiratory
volume in one second (FEV1), maximum mid-expiratory flow
(FEF25-75) and specific airway conductance (Gaw/VL)
2. Exhaled nitric oxide concentration (FeNO)
OBJECTIVES
1. To identify all published randomised controlled trials of

caffeine in the management of asthma. Secondary outcomes
1. Forced vital capacity (FVC)

2. To assess the methodological quality of these randomised
2. Maximal expiratory flow rates at 25% and 50% of vital
controlled trials.
capacity (Vmax50 and Vmax25 respectively)
3. To estimate the overall effect of caffeine upon lung function 3. Exercise-induced bronchoconstriction
and exhaled nitric oxide (FeNO). 4. PC20
5. Carbachol challenge
4. To test whether there is a need to control for caffeine
6. Pulse
consumption prior to lung function testing and testing exhaled
7. Blood pressure
nitric oxide (FeNO).
8. Symptoms
5. To examine the need for further research into the effects of 9. Serum caffeine levels
caffeine in asthma. 10. Side effects and adverse effects.

Search methods for identification of studies but for the 2009 update we have used paired t-test results with
Generic Inverse Variance pooling. In addition, since no results
were reported from parallel-group studies, there was no need to
Electronic searches provide subgroup analyses on the basis of design.
We identified trials using the Cochrane Airways Group Spe- We entered extracted data into the Cochrane Collaboration soft-
cialised Register of trials (CAGR), which is derived from system- ware program (RevMan 5.1).
atic searches of bibliographic databases including the Cochrane In one paper (Bukowskyj 1987) the mean value provided in the
Central Register of Controlled Trials (CENTRAL), MEDLINE, table and that in the corresponding figure were inconsistent (value
EMBASE, CINAHL, AMED and PsycINFO, and handsearching for % change FEF25-75 at 0.5 hours); this was assumed to be a
of respiratory journals and meeting abstracts (see Appendix 1). We misprint and therefore omitted from the meta-analysis.
searched all records in the Specialised Register coded as ’asthma’
using the following terms:
Assessment of risk of bias in included studies
caffeine* or *caffeine or coffee or tea or chocolate or cola.
We did not exclude trials on the basis of language. We searched For this 2009 update, two of us (EW and CC) updated the risk of
the CAGR up to August 2011. bias according to four domains:
1. allocation generation and concealment;
2. blinding;
Searching other resources 3. handling of missing data; and
We reviewed reference lists of all primary studies and review articles 4. selective reporting bias.
for additional references. For each domain we judged the risk of bias as being high, low
We contacted authors of identified trials and asked them to identify or unclear risk of bias in line with recommendations from the
other published and unpublished studies. Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2008).
Data collection and analysis

Measures of treatment effect
We reported individual and pooled statistics as odds ratios (OR)
Selection of studies with 95% confidence intervals (95% CI). We used weighted mean
Two of us (AB, EB) independently reviewed the title, abstract and difference (MD) when identical units of measurement were re-
key words of the references obtained from the literature search. ported. To allow the combination of studies where different units
For the 2009 and 2011 update this was done by EJW and CC. We (e.g. actual values, change scores, % predicted values) were re-
ported for a particular pulmonary function test (e.g. FEV1 or
excluded all studies that were not randomised trials or that clearly
FEF25-75), we performed analyses using the standardised mean
did not fit the inclusion criteria. Two of us reviewed the full text
of the remaining articles. Complete agreement was achieved at all difference (SMD).
stages.
Unit of analysis issues
Data extraction and management Outcomes were measured and reported at a variety of different
We contacted trial authors in an effort to obtain raw and missing time points and following different doses of caffeine. For the pur-
data for the original review. Two of us (AB, EB) independently poses of this review and meta-analysis, we grouped data for each
extracted means and standard deviations or standard errors. We outcome according to time of measurement. We divided data into
converted standard errors to standard deviations. Two research three time frames labelled as follows: ’short’ (less than or equal
staff from the Division of Physiological Medicine, St. George’s to two hours); ’medium’ (greater than two hours and less than or
Hospital Medical School (Sally Spencer and Catherine O’Leary) equal to four hours); and ’long’ (greater than four hours). In the
extracted data visually from graphs. There was little variation in 2009 review a comparison of all doses at two hours was included;
the data extracted by the four review authors. We used the mean where no data at two hours were given we used the nearest data
figures from the four independently extracted sets in this review. point and recorded the time in Table 1.
Only data from cross-over studies were available for inclusion in
this review. Since caffeine is a short-acting agent and most studies
reported washout periods, ’carryover’ and ’period’ effects were not Dealing with missing data
considered to affect the results in an important way. They were Since the trials were run over a few hours there were few dropouts.
treated as parallel designs in the analyses for the original review, Out of a total of 75 patients only six dropped out.

Data synthesis One study (Taylor 2004) assessed the effects of coffee on exhaled
We analysed continuous data using the inverse-variance fixed-ef- nitric oxide (FeNO).
fect method in RevMan 5.1.
Participants
Subgroup analysis and investigation of heterogeneity There were 55 (39 male) adult participants in the six included stud-
For each outcome in each time frame, we performed subgroup ies testing for pulmonary function in the original review. These pa-
analyses to test for differences between ’high’ and ’low’ doses of tients were all described as having stable, mild to moderate asthma.
caffeine. Using the median value to divide the data, we defined Further details of baseline lung function are found in Table 1.
doses as: ’high’ (greater than 5 mg/kg (mg per kg of body weight)); There were 20 adult participants (gender not specified) in the
or ’low’ (lower than 5 mg/kg). study testing for exhaled nitric oxide included in the 2009 update.
The severity of their asthma was not described, but there were 10
steroid-naive and 10 steroid-treated patients.
RESULTS Interventions
Caffeine and matched placebos were administered orally (as a so-
lution = three studies, capsule = two studies, decaffeinated coffee
Description of studies
plus caffeine = one study, caffeine versus decaffeinated coffee =
See: Characteristics of included studies; Characteristics of excluded one study). Two studies contributed to the ’low’ dose comparison:
studies. Bukowskyj 1987 (5 mg/kg) and Colacone 1990 (5 mg/kg). Four
studies contributed to the ’high’ dose comparison: Crivelli 1986
(6 mg/kg), Duffy 1991 (10 mg/kg), Gong 1986 (7.2 mg/kg) and
Results of the search Kivity 1990 (7 mg/kg).
An all years literature search to 2011 returned 23 references. We One study, Taylor 2004, assessed drinking a cup of coffee (inter-
discarded 13 on the basis of the title, abstract or title and abstract. vention group) versus decaffeinated coffee (placebo group) pre-
We obtained full papers for the remaining 10 references. We iden- pared using a standard quantity (15 g) of either caffeine-contain-
tified 17 additional references by searching the bibliographies of ing coffee or decaffeinated coffee.
the retrieved studies.
Seven trials fulfilled the inclusion criteria and were included in
this review. Complete agreement was achieved between the review Outcomes
authors. Pulmonary function tests were the only outcomes suitable for entry
into the meta-analysis.
See Characteristics of included studies for details of secondary
Included studies
outcomes of trials.
Six studies were included in the original review and an update
search conducted in August 2009 identified one additional study
which met the inclusion criteria (Taylor 2004). All studies are Excluded studies
outlined in the Characteristics of included studies table. From examination of the full papers of the of the potentially eligi-
Six studies tested for the effects of caffeine on pulmonary function, ble references, we excluded two studies (Becker 1984; Henderson
although the main aim of these studies differed. Three studies of 1993). One potentially eligible reference was returned from the
these six additionally tested the influence of caffeine on bronchial bibliographic search and this was excluded on retrieval of the full
provocation challenge tests, one using histamine (Colacone 1990), paper (Simmons 1983). See Characteristics of excluded studies.
one carbachol (Crivelli 1986) and one using eucapnic voluntary
hyperventilation (EVH) (Duffy 1991). We did not include chal-
lenge test data in this review. One study also tested the effect of
caffeine on exercise-induced bronchoconstriction (Kivity 1990).
Risk of bias in included studies
One study also compared caffeine to aminophylline (Gong 1986), Complete agreement was reached by the review authors for both
but these data were not analysed as it was considered to be beyond assessments. See Characteristics of included studies for ’Risk of
the scope of this review. bias’ tables for individual studies and Figure 1 for an overview.

Figure 1. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included
study.

Allocation
’medium’ (mean difference (MD) 12.66; 95% CI -0.34 to 25.67;
All the papers stated that the trials were randomised. One trial two studies on 34 participants), ’long’ (MD 11.00; 95% CI -
reported computerised sequence generation which was judged to 6.49 to 28.49; one study on 16 participants).
have a low risk of bias (Gong 1986), while the remaining six trials • Maximum mid-expiratory flow (FEF25-75): ’short’ (MD
were unclear. Two trials reported adequate allocation concealment 25.14; 95% CI 11.92 to 38.37; two studies on 34 participants),
(Bukowskyj 1987; Colacone 1990) while the remaining five were ’medium’ (MD 32.72; 95% CI 16.26 to 49.17; two studies on
unclear. 34 participants), ’long’ (MD 26.00; 95% CI 5.02 to 46.98; one
study on 16 participants).
• Specific airway conductance (Gaw/VL): ’short’ (MD 30.30;
Blinding
95% CI 1.08 to 59.52; one study on 18 participants).
All the studies were described as double-blind. Blinding of the
patient is important so that they put the same effort into lung An improvement was seen for all outcomes after ingesting caffeine
function testing regardless of intervention, however they would compared to placebo at all recorded time frames. This effect was
presumably be able to detect if they had ingested any caffeine due statistically significant in all cases except for FEV1 at the ’medium’
to side effects. Five studies were judged to have a low risk of bias and ’long’ time frames where the confidence intervals crossed the
with respect to blinding (Bukowskyj 1987; Colacone 1990; Duffy line of no effect.
1991; Gong 1986; Kivity 1990). None of the papers described
blinding of the investigator administering the caffeine or placebo
Subgroup analysis: ’low’ dose
to the patient or the investigator taking the outcome readings.
Two studies on 36 participants reported FEV1 outcomes at ’low’
dose. Data for the three time frame comparisons came from the
Incomplete outcome data following number of studies: ’short’ = two studies, ’medium’ = one
Since the trials took place over relatively short time frames there study, ’long’ = one study. For FEF25-75 only one study on 16
were few dropouts and only one missing data point throughout participants contributed data at all time frames. There were no
all the studies. All trials were judged to be of low risk of bias with data for Gaw/VL at this dose.
respect to dealing with incomplete data. All lung function parameters tended to improve post caffeine in-
gestion compared to placebo. For FEV1, this effect was clear only
at the ’short’ time frame. For FEF25-75, the difference was clear
Other potential sources of bias at all times.
All the included studies used a cross-over design. In all cases the
cross-over rule was time. The time period between study days was Subgroup analysis: ’high’ dose
not always stated but, where details were provided, ranged from
consecutive days to within two weeks. To control for the effects of Four studies on 42 participants reported FEV1 outcomes at ’high’
circadian rhythms, tests took place at the same time on each day dose. Data were available for the meta-analysis from two studies
in all studies. Few studies comment on the existence or effect of at the ’short’ and one study at the ’medium’ time frame. No FEV1
outlying values. data were reported at the ’long’ time frame. For FEF25-75, one
study on 16 participants only contributed data at the ’short’ and
’medium’ time frames. One study provided data for Gaw/VL at
Effects of interventions the ’short’ time frame only.
Lung function was found to improve following a ’high’ dose of
caffeine compared to placebo for all measured outcomes. This
Outcomes relating to lung function effect was clear at the ’short’ time frame only for FEV1 and FEF25-
The description of the analysis will follow the list of comparisons 75. A clear improvement in Gaw/VL was also seen at the ’short’
used in this Cochrane Review and will concentrate on caffeine time frame.
versus placebo results. Subgroup analyses will highlight the ’low’ Two other studies (Crivelli 1986; Duffy 1991) tested the effect of
dose versus ’high’ dose and time of final assessment comparisons. ’high’ dose caffeine at the ’short’ time frame on FEV1, but no data
Results: were extracted for inclusion into the meta-analysis in the origi-
• Forced expiratory volume in one second (FEV1): ’short’ nal review. However, in correspondence, both authors reported
(standardised mean difference (SMD) 0.72; 95% confidence no significant difference in bronchodilation between caffeine and
interval (CI) 0.25 to 1.20; six studies on 78 participants), placebo ingestion. For the 2009 update, data were extracted from

Crivelli 1986 from the original patient data provided into FEV1 the outcome data between studies.
outcomes at two hours. For this update we entered the paired t-test results into the review
using Generic Inverse Variance pooling for the two-hour FEV1
outcome. The confidence intervals for each trial were fairly similar
Subgroup analysis: FEV1 outcomes at two hours to those found previously, when the results had not been analysed
In order to draw an overall conclusion we felt that it would be with paired t-tests. This provides reassurance that the previous
helpful to have a comparison with as many studies side by side conclusions of the review are valid.
as possible (2009 update). Peak FEV1 readings were recorded at When analysed as % change in FEV1 the pooled result of three
around two hours, so this was chosen as the best time point (see trials on 26 participants showed a significant benefit with caffeine
Table 1). Crivelli 1986 reported a reading of FEV1 at 45 minutes at higher dose (MD 5.47%; 95% CI 1.43 to 9.52, Analysis 1.9)
rather than two hours and these data were included in the meta- (see Figure 2). There was significant heterogeneity in this result
analysis. Data were extracted from the patient data provided in (I2 = 61%), but this appears to come from Crivelli 1986; the
Crivelli 1986. Five studies on 88 participants gave FEV1 readings participants in this trial were asymptomatic and not on treatment
at ’high’ doses and one study on 20 participants gave an additional for asthma, so would have little potential to increase their FEV1
reading at ’low’ dose (Analysis 1.8). The forest plot shows im- following caffeine. If the results of the two other trials (Bukowskyj
proved FEV1 when patients had consumed caffeine at high dose 1987; Gong 1986) are combined this gives a larger mean difference
prior to testing (SMD 0.76; 95% CI 0.32 to 1.20). There was no with caffeine of around 15% difference in FEV1 (MD 14.54%;
heterogeneity in the result (I2 = 0) indicating a good agreement in 95% CI 5.35 to 23.72).
Figure 2. Forest plot of comparison: 1 All caffeine doses (highest dose from each study) versus placebo,
outcome: 1.10 FEV1 outcomes at 2 hours (High dose).
The papers differed in their reporting of serum caffeine levels.

After a dose of caffeine (5 mg/kg), Bukowskyj 1987 reported a
Serum caffeine levels
peak serum level of 8.7 (SD = 1.7) µg/mL one hour after ingestion.

Colacone 1990 used the same dose and reported a mean (but not significant after two hours. In contrast, for FEF25-75 the effect
peak) level at 1 hour 45 minutes of 5.4 (SD = 1.23) µg/mL. Duffy was clear at all times, even over four hours. A clear increase follow-
1991 reported that peak serum levels of caffeine (mean 18.8; 95% ing a ’high’ dose of caffeine (> 5 mg/kg) compared to placebo was
CI 12.4 to 25.2 mg/L at 45 minutes) were observed 45 to 60 seen in FEV1, FEF25-75 and Gaw/VL at up to two hours only.
minutes after ingestion of caffeine (10 mg/kg). Gaw/VL outcomes were not recorded beyond two hours. At two
Taylor 2004 reported that at 60 minutes, serum caffeine levels hours, at all doses, there was an improvement in lung function
were higher after ingesting regular caffeine-containing coffee than after ingesting caffeine, and when reported as % increase in FEV1
after decaffeinated coffee at 60 minutes (3.9 versus 0.4 mg/mL this showed an average difference of 5% change (MD 5.47%; 95%
respectively). Statistical tests of significance were only reported for CI 1.43 to 9.52). However when the study on patients who were
within-group differences. asymptomatic and on no treatment (Crivelli 1986) was excluded,
the change in FEV1 was higher after caffeine (MD 14.54%; 95%
CI 5.35 to 23.72).
Side effects and adverse effects The size of improvements in lung function were small and at the
Five of the studies commented on side effects, including heart margins of what would normally be considered clinical significance
rate and blood pressure changes although none contributed data (FEV1: maximum 13.7% change from baseline (Gong 1986) or
that could be entered in a meta-analysis. No side effects were maximum 330 mL absolute change for caffeine versus placebo
reported after ’low’ doses of caffeine. After ingestion of a ’high’ (Kivity 1990)). Only one study (Gong 1986) explicitly recorded
dose of caffeine two patients reported mild tremor (Kivity 1990), the patients’ perception: four of the nine participants reported
three patients reported nervousness and gastrointestinal upset ( improved breathing following ingestion of a ’high’ dose of caffeine;
Gong 1986), and one patient withdrew from the study because the same information was not provided for the placebo group.
of nervousness and agitation (Duffy 1991), which was presumed Concerns have been raised as to whether caffeine interferes with the
to be due to the caffeine. Only one study (Gong 1986) reported measurement of exhaled nitric oxide levels, based on a randomised
significant changes in heart rate (a decrease up to 9%) and blood study in non-asthmatic healthy volunteers (Bruce 2002). The only
pressure (an increase up to 12%). randomised study to date in a small sample of people with mild
asthma did not identify a significant difference between a cup of
coffee made with 15 g of grounds and a similar cup made with
Outcomes relating to exhaled nitric oxide decaffeinated coffee (Taylor 2004). Additional studies would help
The impact of caffeine on FeNO was assessed in one study on 20 to determine whether this finding is valid.
participants (Taylor 2004). This small study reported no signifi-
cant difference in exhaled nitric oxide (data reported in the text
as non-significant (P = 0.38) and presented graphically). Findings Overall completeness and applicability of
were not significantly different in subgroups for those treated with evidence
inhaled steroids and those not treated with steroids.
Comparison of the findings across studies was complicated by the
use of five different doses of caffeine, different outcome measures
recorded at different times, and different methods of reporting
outcomes. To permit the aggregation of data we grouped the trials
DISCUSSION according to dose and time. Similarly, we made analyses using the
The available evidence of the effect of caffeine compared to placebo SMD where the combined trials used different units of measure-
on lung function and exhaled nitric oxide from randomised con- ment for the same variable. Despite this, few data were available
trolled trials is summarised in this systematic review. to be combined in the meta-analysis.
The dose of caffeine tested varied greatly between studies, from 5
to 10 mg/kg. In an effort to make this more meaningful in dietary
Summary of main results terms, most authors related doses to cups of coffee. However, the
For all dose strengths, caffeine compared to placebo was found to average amount of caffeine per cup is quoted as between 30 to 150
significantly improve lung function measured in terms of FEV1, mg, although 150 mg was most commonly stated. Consequently,
FEF25-75 and Gaw/VL for up to two hours post ingestion. This the number of cups of coffee required to produce bronchodilation
effect was sustained for FEF25-75 for over four hours. Improve- is reported from one to five cups.
ment was also seen in FEV1 up to this time, however this effect One method of standardising the dose ingested between studies
did not reach statistical significance. No data were available for would be to examine the peak serum levels. The reported peak
Gaw/VL after two hours. Bronchodilation was also seen after in- serum levels vary greatly: from 5.4 mg/L (Colacone 1990) to 18.8
gesting caffeine even following a ’low’ dose (5 mg/kg). For FEV1, mg/L (Duffy 1991). Interestingly, the study reporting serum caf-
the difference between the caffeine and placebo groups was not feine level of 18.8 mg/L after a dose of caffeine (10 mg/kg) found

no increase in FEV1, although a later protective effect against cases reported to be randomised, none of the authors assessed or-
bronchoconstriction post broncho provocation challenge test was der effects, and only two authors explicitly stated that the patients
found (Duffy 1991). These data were not presented in a way that could not discern which treatment they had received (Bukowskyj
would enable extraction for entry into the meta-analysis. Peak 1987; Gong 1986). Sample sizes were small and the existence or
serum levels of caffeine tended to occur at 45 or 60 minutes effect of outlying values were rarely discussed. Outlying values are
post caffeine intake. However, a clear difference between caffeine important in small studies using cross-over designs, as each subject
and placebo was seen even four hours post ingestion (Bukowskyj provides a large proportion of the data.
1987). Few studies reported measurements beyond four hours post This review was restricted to an analysis of clinically relevant data
dosing. However, serum caffeine was detected in some patients at in terms of a patient response and excluded the scientific issue of
baseline. It is not known whether this would affect the potential for whether caffeine affects airway response to bronchoconstricting
bronchodilation, especially where lung function outcomes were agents.
reported in terms of change from baseline. Even consideration of
the peak serum levels would not fully compensate for this.
The findings of any review are only applicable to the characteristics
Potential biases in the review process
of the participants taking part in the included studies. Although
a standardised definition was not used across the studies, partici- The possibility of publication bias (non-publication of negative
pants were described as having mild or moderate asthma, therefore studies) should be considered given that only small differences in
results may not be generalisable to those with more severe asthma. bronchodilator effect were found between caffeine and placebo.
Most subjects were described as having stable or asymptomatic However, we used a comprehensive search strategy and searched
asthma, but how this was assessed was not described. Similarly, for unpublished trials in an attempt to minimise this bias.
patients’ treatment regimens varied greatly across the trials and the
effect of this was not studied.
It could be argued that insufficient data were presented on side
Agreements and disagreements with other
effects resulting from caffeine, however the studies were designed
studies or reviews
not to asses the long-term effects of caffeine, but instead to as-
sess the short-term impact of ingesting caffeine on lung function There are no other published reviews.
and exhaled nitric oxide tests. The side effects of caffeine are sim-
ilar to those of theophylline (tachycardia, palpitation, nausea and
other gastrointestinal disturbances, headache, central nervous sys-
tem stimulation, insomnia).
AUTHORS’ CONCLUSIONS
The issue arising from this review is not whether caffeine should
or should not be used as a bronchodilator in preference for theo-
phylline or whether the side effects are sufficient to override this
Implications for practice
benefit. Instead the issue is whether or not the amount of caffeine Caffeine, even at ’low’ doses, has been found to improve lung
ingested in a cup of coffee (or two) is sufficient to alter the result function for at least four hours after ingestion. One trial using the
of a lung function test. This may be important if coffee drinkers most sensitive outcome measurements (FEF25-75) showed that
show better results in lung function tests than they would achieve effects are sustained for over four hours post ingestion. It is there-
if they did not drink coffee. The evidence presented here shows fore recommended that patients be advised to withhold caffeine
that taking a ’normal’ amount of caffeine, equivalent to one to for at least four hours prior to lung function testing. Alternatively
five cups of coffee, is enough to alter the results of a lung func- lung function tests results should be considered in light of caffeine
tion test. Therefore patients should be advised not to drink coffee ingested within four hours of the start of the test, as coffee drinkers
for four hours before taking a lung function test. Drinking coffee may present with a better lung function test result than if they had
before taking a FeNO test does not affect the results according not consumed so much caffeine. Caffeine does not appear to have
to the single-study data presented here, although further data are a significant effect on exhaled nitric oxide levels.
necessary to clarify. The long-term impact of drinking coffee was
With regard to advice to patients, caffeine ingestion may improve
not studied in these trials or reviewed here.
lung function in the short term. However, these trial data do not
indicate whether the effect reaches a threshold for clinical signifi-
cance in terms of an improvement of symptoms or quality of life.
Quality of the evidence This was not the purpose of trials examined in this review. It is not
Interpretation of the results of this review must include consider- known if tolerance to the bronchodilatory effects of caffeine devel-
ation of methodological limitations. All of the studies employed ops in habitual consumers, which is a concern given that tolerance
a cross-over design. Although the method of allocation was in all has been found in studies of sleep and renal function (Curatolo

1983). The amount of dietary caffeine required and the true ben- 4. The response to caffeine of people with well-controlled
efit of dietary caffeine intake would be difficult to calculate due to asthmatics on anti-inflammatory agents. Asthmatics using
the varying levels of caffeine within different foods and beverages. inhaled steroids may be less responsive and this needs further
It appears that a substantial intake of caffeinated products would evaluation.
be needed to achieve a beneficial bronchodilatory effect and that
5. Differences in the bronchodilator effects of caffeine
possible undesirable side effects may outweigh the benefits.
between habitual consumers and non-consumers.
Implications for research 6. Whether caffeine ingestion alters management decisions in

asthma (based on lung function measurements).
That caffeine has a bronchodilatory effect in asthma is clear from
existing research. Future studies could address the following.
1. Patients’ perception of the effect of caffeine on their asthma

and quality of life, as this has not been systematically studied. ACKNOWLEDGEMENTS
We would like to thank Steve Milan and Jane Dennis for all their
2. The maximum length of time at which bronchodilation is
help, Brian Rowe and Paul Jones for their editorial input, and
sustained, as this cannot be determined from existing trials.
Sally Spencer and Catherine O’Leary for their assistance with the
3. Effects on patients with different levels of asthma severity, data extraction. We would also like to thank all the authors who
since existing trials have only studied people with mild to responded to our enquiries: Dr E. Simons, Dr M. Bukowskyj, Dr
moderate asthma. A. Colacone, Dr S. Kivity, Dr H. Gong and Dr F. O’Connell.
REFERENCES
References to studies included in this review asthma [Abstract]. European Respiratory Journal 2003;22
(Suppl 45):P1165.
∗
Bukowskyj 1987 {published data only} Taylor ES, Smith AD, Cowan JO, Herbison GP, Taylor
Bukowskyj M, Nakatsu K. The bronchodilator effect of DR. Effect of caffeine ingestion on exhaled nitric oxide
caffeine in adult asthmatics. American Review of Respiratory measurements in patients with asthma. American Journal
Disease 1987;135(1):173–5. of Respiratory and Critical Care Medicine 2004;169(9):
Colacone 1990 {published data only} 1019–21.
Colacone A, Bertolo L, Wolkove N, Cohen C, Kreisman References to studies excluded from this review
H. Effect of caffeine on histamine bronchoprovocation in
asthma. Thorax 1990;45(8):630–2.
Becker 1984 {published data only}
Crivelli 1986 {published data only} Becker AB, Simons KJ, Gillespie CA, Simons FE. The
Crivelli M, Wahllander A, Jost G, Preisig R, Bachofen H. bronchodilator effects and pharmacokinetics of caffeine in
Effect of dietary caffeine on airway reactivity in asthma. asthma. New England Journal of Medicine 1984;310(12):
Respiration 1986;50(4):258–64. 743–6.
Duffy 1991 {published data only} Henderson 1993 {published data only}
Duffy P, Phillips YY. Caffeine consumption decreases the Henderson JC, O’Connell F, Fuller RW. Decrease of
response to bronchoprovocation challenge with dry gas histamine induced bronchoconstriction by caffeine in mild
hyperventilation. Chest 1991;99(6):1374–7. asthma. Thorax 1993;48(8):824–6.
Gong 1986 {published data only} Simmons 1983 {published data only}
Gong H Jr, Simmons MS, Tashkin DP, Hui KK, Lee EY. Simmons M, Gong H, Tashkin DP, Hui K, Lee E.
Bronchodilator effects of caffeine in coffee. A dose-response Bronchodilator effects of coffee in asthmatics. Chest 1983;
study of asthmatic subjects. Chest 1986;89(3):335–42. 84:332.
Kivity 1990 {published data only} References to studies awaiting assessment

Kivity S, Aharon YB, Man A, Topilsky M. The effect of
caffeine on exercise-induced bronchoconstriction. Chest Yurach 2011 {published data only}
1990;97(5):1083–5. Yurach MT, Davis BE, Cockcroft DW. The effect of
Taylor 2004 {published data only} caffeinated coffee on airway response to methacholine
Taylor E, Smith AD, Herbison GP, Cowan JO, Taylor DR. and exhaled nitric oxide. Respiratory Medicine 2011;105:
Effect of caffeine on exhaled nitric oxide measurements in 1606–10.
Additional references Pagano 1988
Pagano R, Negri E, Decarli A, La Vecchia C. Coffee
drinking and prevalence of bronchial asthma. Chest 1988;
Bruce 2002 94(2):386–9.
Bruce C, Yates DH, Thomas PS. Caffeine decreases exhaled
RevMan 5.1
nitric oxide. Thorax 2002;57:361–3.
Copenhagen, The Nordic Cochrane Centre: The Cochrane
Cheney 1935 Collaboration. Review Manager (RevMan) Version 5.1.
Cheney RH. Ventricular response in caffeine-nicotine Copenhagen, The Nordic Cochrane Centre: The Cochrane
antagonism. Journal of Pharmacology and Experimental Collaboration, 2011.
Therapeutics 1935;54(1):42–52. Robertson 1978
Robertson D, Frolich JC, Carr RK, Watson JT, Hollifield
Curatolo 1983 JW, Shand DG, et al.Effects of caffeine on plasma renin
Curatolo PW, Robertson D. The health consequences of activity, catecholamines and blood pressure. New England
caffeine. Annals of Internal Medicine 1983;98(1):641–53. Journal of Medicine 1978;298:181–6.
Stephenson 1977
Grollman 1930
Stephenson PE. Physiologic and psychotropic effects of
Grollman A. The action of alcohol, caffeine, and tobacco,
caffeine on man. Journal of the American Dietetic Association
on the cardiac output (and its related functions) of normal
1977;71:240–7.
man. Journal of Pharmacology and Experimental Therapeutics
1930;39(3):313–27. Woodcock 1981
Woodcock AA, Gross ER, Gellert A, Shah S, Johnson
Higgins 2008 M, Geddes DM. Effects of dihydrocodeine, alcohol, and
Higgins JPT, Green S, editors. Cochrane Handbook for caffeine on breathlessness and exercise tolerance in patients
Systematic Reviews of Interventions Version 5.0.1 [updated with chronic obstructive lung disease and normal blood
September 2008]. The Cochrane Collaboration, 2008. gases. New England Journal of Medicine 1981;305:1611–6.
∗
Available from www.cochrane-handbook.org. Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Bukowskyj 1987
Methods Randomised controlled trial

Cross-over design - double-blinded, rule = time (1 week)
Participants Ten patients admitted, 8 (4 male) completed the study

Mean age 64.8 (SD = 8) years
Severity of asthma:
Inclusion criteria: reversible obstructive airway disease, clinically stable, FEV1 < 75%
predicted value
Exclusion criteria: congestive heart failure, hepatic disease, ingestion of cimetidine, in-
gestion of oral contraceptives
Prescribed medication: 7 patients took oral theophylline and salbutamol; 3 patients took
inhaled beclomethasone dipropionate; 1 patient took inhaled beclomethasone dipropi-
onate and prednisolone
Control measure: refrained from caffeine, other methylxanthine-containing substances
and orally-administered beta-agonists for 12 h prior to and throughout 8 h study. Re-
frained from inhaling beta-agonists for 6 h prior to and throughout the 8 h study period
Interventions 5 mg/kg caffeine versus placebo as a solution in a juice drink
Outcomes % change FEV1, % change FVC, % change FEF25-75, % change Vmax50, % change
Vmax25, FEV1 % predicted, pulse, blood pressure
Notes Administration of corticosteroids was continued unchanged in those patients receiving

long-term therapy with these drugs
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Unclear risk No details

bias)
Allocation concealment (selection bias) Low risk Allocated by pharmacist
Blinding (performance bias and detection Low risk Quote: “Double-blinded”

bias) Quote: “The medication code was known
All outcomes only to the hospital pharmacists.”
Incomplete outcome data (attrition bias) Low risk Quote: “The two patients who withdrew
All outcomes did so because they found the repeated
spirometric tests unacceptably tiring. There
was one patient who completed the study
except for the last four h of the placebo day

Bukowskyj 1987 (Continued)
when she developed dyspnoea.”

No data used from these patients
Colacone 1990

Cross-over design, rule = time (variable, within 2 weeks)
Participants Ten adults (7 male) completed the study

Mean age 46 (SD = 17) years
Asthma severity: mild. Nine patients had previously documented increased airways re-
activity and one had seasonal asthma Symptom-free
Prescribed medication: 7 patients took inhaled beta-agonist, 5 patients took theophylline,
4 patients took inhaled corticosteroid and 2 required no medication
Control measures: no caffeine 48 h before study. Fasted for 8 h. Withheld antiasthmatic
medications according to standard guidelines for histamine broncho provocation testing.
Beta-agonists and anticholinergic drugs withheld for 8 to 12 h and theophylline for
12 h before testing. Slow-release theophylline and antihistamines withheld 48 h before
testing. Steroids continued as normal
Interventions 5 mg/kg caffeine versus placebo in a juice drink solution indistinguishable in taste and
smell
Histamine broncho provocation challenge
Outcomes Change in FEV1, PC20
Notes
Risk of bias

bias)
Allocation concealment (selection bias) Low risk Allocated by pharmacist
Blinding (performance bias and detection Low risk Quote: “Caffeine and correspond-
bias) ing placebo were prepared in solution and
All outcomes coded by the hospital pharmacy.”
Quote: “Both solutions were indistinguish-
able by taste, colour and smell.”
Incomplete outcome data (attrition bias) Low risk No dropouts

All outcomes

Crivelli 1986

Cross-over design rule = time (2 consecutive days)
Participants Seven adults (6 male) completed the study

Age range 27 to 40 years
Asthma severity: asymptomatic
Included: patients with documented asthmatic airway obstruction
Excluded: pregnant women asthmatic patients with concomitant liver and/or cardiovas-
cular diseases, and patients treated with drugs affecting the hepatic microsomal enzyme
system (barbiturates, phenytoin, rifampicin etc.)
Prescribed medication: no bronchodilators, sodium cromoglycate or steroids for at least
2 weeks before the investigation
Control measures: withheld all caffeine and methyl xanthine-containing foods and bev-
erages at least 12 h prior to the experiment
Interventions 6 mg/kg caffeine versus placebo. Orange juice drink containing caffeine or a placebo
drink containing solvent, i.e. saline
Carbachol challenge
Outcomes FEV1, SGaw
Notes
Risk of bias

bias)
Allocation concealment (selection bias) Unclear risk Method of allocation unknown
Blinding (performance bias and detection Unclear risk Described as “double-blind” but caffeine or
bias) saline given in orange juice so may not have
All outcomes tasted the same

All outcomes
Duffy 1991

Cross-over design - double-blinded, rule = time (not stated)
Participants 12 adults (11 male) admitted, 11 males completed the study

Age range 18 to 42 years
Inclusion criteria: FVC and FEV1 > 80% predicted and at least 10% fall in FEV1
in response to EVH (eucapnic voluntary hyperventilation) broncho provocation. Non-
smokers
Duffy 1991 (Continued)
Exclusion criteria: upper respiratory tract infection or influenza vaccination within 6

weeks before testing, an episode of asthma requiring hospitalisation or steroids within
the previous 6 weeks before testing, pregnancy, or other cardiovascular disease apart from
asthma
Prescribed medication: no daily asthma medication
Control measures: refrain from caffeine and methylxanthine-containing substances for
12 hours, and food and cigarettes for 4 hours before testing
Interventions 5 mg/kg, 10 mg/kg, placebo

EVH broncho provocation
Outcomes FEV1, FVC, % dFEV (the percentage fall in FEV1, after EVH)
Notes Quote: 8 of 11 subjects had detectable caffeine levels on the day placebo was given,
despite explicit instructions for avoidance of xanthine-containing products
Risk of bias

bias)
Allocation concealment (selection bias) Unclear risk Quote: “on three separate test days, each
individual received, in random order, either
placebo, 5 mg/kg caffeine or 10 mg/kg caf-
feine.”
Blinding (performance bias and detection Low risk Quote: “After baseline pulmonary func-
bias) tion tests, caffeine was given in a ran-
All outcomes domised, crossover, double blind fashion.
Gelatin capsules were administered which
contained either 0 mg, 5 mg/kg or 10 mg/
kg caffeine.”
Incomplete outcome data (attrition bias) Low risk Dropout = 1 (female), due to side effects
All outcomes of nervousness and agitation presumably
from the caffeine
Gong 1986
Methods Randomised controlled trial. Method of allocation computer program

Cross-over design - double-blinded, rule = time (at least 3 days)
Participants Nine (4 male)

Mean age = 35 (SD = 17) years
Inclusion criteria: stable asthma (ATS criteria), 12 years of mild to moderately severe
asthma, allergic in nature for 7 subjects, no other clinically evident disorders including

Gong 1986 (Continued)
hepatic disease or hypertension

Exclusion criteria: no subject was receiving immunotherapy
Prescribed medication: 7 = theophylline, 8 = sympathomimetic agents, 3 = inhaled
corticosteroids, 1 = oral corticosteroids, 1 = cromolyn sodium
Control measures: fasted for 4 hours prior to study and withheld the following prior to
each day of study: theophylline compounds (48 h); adrenergic agents, oral (12 h) and
inhaled (8 h); corticosteroids, oral (24 h) and inhaled (12 h); cromolyn sodium (24 h);
antihistamines (48 h); caffeine-containing beverages and medications (12 h)
Interventions Decaffeinated coffee (containing ~13 mg caffeine) plus a capsule containing amino-
phylline (200 mg)
Decaffeinated coffee (containing ~13 mg caffeine) plus a placebo (lactose) capsule
Decaffeinated coffee with additional 150 mg caffeine plus a placebo (lactose) capsule
Outcomes % change FEV1, FVC, FEF25-75, Gaw/VL (results given only for 7.2 mg/kg caffeine
versus placebo + 200 mg aminophylline). Sampling of venous blood, whole body plethys-
mography, spirometry, respiratory rate, heart rate, sitting blood pressure, and symptoms
Notes
Risk of bias
Random sequence generation (selection Low risk Randomised by computer program

bias)
Allocation concealment (selection bias) Unclear risk No details
Blinding (performance bias and detection Low risk Although they went to lengths to blind the
bias) patients, there was no indication of method
All outcomes for blinding investigators

All outcomes
Kivity 1990

Cross-over design - double-blinded, rule = time (within 2 weeks)
Participants 13 admitted, 10 adults (7 male) completed the study

Mean age = 19.5 (SD = 1.1) years
Inclusion criteria: documented reversible obstructive airway disease with a 20% im-
provement in either FVC or FEV1 after bronchodilator therapy, exercise-induced drop
in FEV1 of ≥ 15% from baseline, all patients clinically stable

Kivity 1990 (Continued)
Exclusion criteria: any other chronic illness or receiving medication other than for
bronchial asthma
Prescribed medication: 2 = slow release theophylline, 10 = inhaled salbutamol. None of
the patients were receiving corticosteroids, cromolyn sodium or ketotifen
Interventions Opaque placebo capsule or opaque 3.5 mg/kg caffeine capsule or opaque 7 mg/kg caffeine
capsule taken with 100 mL water.
Exercise-induced bronchoconstriction
Outcomes FEV1, pulse, blood pressure
Notes Patients refrained from caffeine for 12 h, from theophylline containing drugs for 48 h,
and from inhaled beta-agonists 8 h prior to the study. The patient did not have caffeinated
drinks 24 h prior to the study day (conflicting information in paper). The patients did
not eat during the study
Risk of bias

bias)
Allocation concealment (selection bias) Unclear risk No details
Blinding (performance bias and detection Low risk Quote: “Caffeine and placebo were given
bias) through an opaque capsule together with
All outcomes 100 mL of water.” Stated double-blind
Incomplete outcome data (attrition bias) Low risk Quote: “three patients who withdrew from
All outcomes the study could not comply with multiple
visits to the clinic”. No data used from these
patients
Taylor 2004
Methods Randomised, double-blind, cross-over trial
Participants 20 adults (gender not specified) completed the study

Mean age: 37 (range 16 to 73) years
Inclusion criteria: regular coffee drinkers; FeNO > 10 PPB. 10 steroid-naive and 10
treated with ICS (mean dose 980 µg/d)
Exclusion criteria: oral prednisone, oral theophylline or inhaled long-acting beta-agonist
for 1 month prior to study
Control measures: caffeine withheld for 24 h. Inhaled bronchodilators withheld 6 h
Interventions Intervention: 15 g caffeine-containing coffee (Illy Espresso Caffe Macinato) prepared in

an espresso coffee maker as a 200 mL cup of coffee

Taylor 2004 (Continued)
Placebo: 15 g decaffeinated coffee (Illy Espresso Decaffeinated Macinato) prepared in

an espresso coffee maker as a 200 mL cup of coffee
Outcomes FeNO
Notes
Risk of bias

bias)
Allocation concealment (selection bias) Unclear risk Stated randomised, no information given
on method used
Blinding (performance bias and detection Unclear risk Stated double-blind, but patient blinding
bias) depends on regular and decaffeinated cof-
All outcomes fee being indistinguishable by taste. No
mention of researcher blinding

All outcomes
ATS: American Thoracic Society

EVH: eucapnic voluntary hyperventilation
FEF25-75: maximum mid-expiratory flow
FEV1: forced expiratory volume in one second
FVC: forced vital capacity
h: hour
ICS: inhaled corticosteroids
PPB: parts per billion
SD: standard deviationVmax25/Vmax50: maximal expiratory flow rates at 25% and 50% of vital capacity
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Becker 1984 Participants are children

Interventions are caffeine versus theophylline
Henderson 1993 Histamine broncho provocation challenge (FEV1 measured after challenge)

(Continued)
Simmons 1983 Not a randomised controlled trial

DATA AND ANALYSES
Comparison 1. All caffeine doses versus placebo
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 FEV1 outcomes at ’short’ time 6 78 Std. Mean Difference (IV, Fixed, 95% CI) 0.72 [0.25, 1.20]
frame
1.1 Low dose 2 36 Std. Mean Difference (IV, Fixed, 95% CI) 0.70 [0.02, 1.38]
1.2 High dose 4 42 Std. Mean Difference (IV, Fixed, 95% CI) 0.75 [0.08, 1.41]
2 FEV1 outcomes at ’medium’ 2 34 Mean Difference (IV, Fixed, 95% CI) 12.66 [-0.34, 25.67]
time frame
2.1 Low dose 1 16 Mean Difference (IV, Fixed, 95% CI) 11.5 [-7.44, 30.44]
2.2 High dose 1 18 Mean Difference (IV, Fixed, 95% CI) 13.7 [-4.18, 31.58]
3 FEV1 outcomes at ’long’ time 1 16 Mean Difference (IV, Fixed, 95% CI) 11.0 [-6.49, 28.49]
frame
3.1 Low dose 1 16 Mean Difference (IV, Fixed, 95% CI) 11.0 [-6.49, 28.49]
3.2 High dose 0 0 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4 FEF 25-75 outcomes at ’short’ 2 34 Mean Difference (IV, Fixed, 95% CI) 25.14 [11.92, 38.37]
time frame
4.1 Low dose 1 16 Mean Difference (IV, Fixed, 95% CI) 23.33 [6.18, 40.48]
5 FEF 25-75 outcomes at 2 34 Mean Difference (IV, Fixed, 95% CI) 32.72 [16.26, 49.17]
’medium’ time frame
5.2 High dose 1 18 Mean Difference (IV, Fixed, 95% CI) 26.20 [-3.89, 56.29]
6 FEF 25-75 outcomes at ’long’ 1 16 Mean Difference (IV, Fixed, 95% CI) 26.0 [5.02, 46.98]
time frame
7 Gaw/VL outcomes at ’short’ 1 18 Mean Difference (IV, Fixed, 95% CI) 30.30 [1.08, 59.52]
time frame
8 FEV1 outcomes at 2 hours 5 Std. Mean Difference (IV, Fixed, 95% CI) Subtotals only
8.1 Low dose 1 20 Std. Mean Difference (IV, Fixed, 95% CI) 0.40 [-0.49, 1.29]
8.2 High dose 5 88 Std. Mean Difference (IV, Fixed, 95% CI) 0.76 [0.32, 1.20]
9 FEV1 outcomes at 2 hours 5 Mean Difference (Fixed, 95% CI) Subtotals only
(High dose)
9.1 % Change in FEV1 3 Mean Difference (Fixed, 95% CI) 5.47 [1.43, 9.52]
9.2 Post-treatment FEV1 litres 1 Mean Difference (Fixed, 95% CI) 0.38 [0.01, 0.75]
9.3 Change in FEV1 litres 1 Mean Difference (Fixed, 95% CI) 0.05 [-0.06, 0.16]

Analysis 1.1. Comparison 1 All caffeine doses versus placebo, Outcome 1 FEV1 outcomes at ’short’ time
frame.
Review: Caffeine for asthma
Comparison: 1 All caffeine doses versus placebo
Outcome: 1 FEV1 outcomes at ’short’ time frame
Std. Std.
Mean Mean
Study or subgroup Caffeine Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Low dose
Bukowskyj 1987 8 14 (16.25) 8 2.25 (11) 21.3 % 0.80 [ -0.23, 1.83 ]
Colacone 1990 10 0.1 (0.09) 10 0.05 (0.06) 27.7 % 0.63 [ -0.28, 1.53 ]
Subtotal (95% CI) 18 18 49.0 % 0.70 [ 0.02, 1.38 ]

Heterogeneity: Chi2 = 0.06, df = 1 (P = 0.80); I2 =0.0%
Test for overall effect: Z = 2.03 (P = 0.043)
2 High dose
Crivelli 1986 1 0 (0) 1 0 (0) Not estimable
Duffy 1991 1 0 (0) 1 0 (0) Not estimable
Gong 1986 9 15.5 (10.9) 9 2.4 (14.6) 23.0 % 0.97 [ -0.02, 1.96 ]
Kivity 1990 10 3.55 (0.55) 10 3.22 (0.57) 28.0 % 0.56 [ -0.33, 1.46 ]
Subtotal (95% CI) 21 21 51.0 % 0.75 [ 0.08, 1.41 ]

Total (95% CI) 39 39 100.0 % 0.72 [ 0.25, 1.20 ]
Test for subgroup differences: Chi2 = 0.01, df = 1 (P = 0.93), I2 =0.0%
-2 -1 0 1 2
Control better Caffeine better

Analysis 1.2. Comparison 1 All caffeine doses versus placebo, Outcome 2 FEV1 outcomes at ’medium’ time
frame.
Outcome: 2 FEV1 outcomes at ’medium’ time frame
Mean Mean
1 Low dose
Bukowskyj 1987 8 14.5 (21) 8 3 (17.5) 47.1 % 11.50 [ -7.44, 30.44 ]
Subtotal (95% CI) 8 8 47.1 % 11.50 [ -7.44, 30.44 ]

Heterogeneity: not applicable
2 High dose
Gong 1986 9 15.5 (12.6) 9 1.8 (24.3) 52.9 % 13.70 [ -4.18, 31.58 ]
Subtotal (95% CI) 9 9 52.9 % 13.70 [ -4.18, 31.58 ]

Total (95% CI) 17 17 100.0 % 12.66 [ -0.34, 25.67 ]
-20 -10 0 10 20

Analysis 1.3. Comparison 1 All caffeine doses versus placebo, Outcome 3 FEV1 outcomes at ’long’ time
frame.
Outcome: 3 FEV1 outcomes at ’long’ time frame
Mean Mean
1 Low dose
Bukowskyj 1987 8 5.5 (21) 8 -5.5 (14) 100.0 % 11.00 [ -6.49, 28.49 ]
Subtotal (95% CI) 8 8 100.0 % 11.00 [ -6.49, 28.49 ]

2 High dose
Subtotal (95% CI) 0 0 Not estimable
Test for overall effect: not applicable
Total (95% CI) 8 8 100.0 % 11.00 [ -6.49, 28.49 ]
Test for subgroup differences: Not applicable
-20 -10 0 10 20

Analysis 1.4. Comparison 1 All caffeine doses versus placebo, Outcome 4 FEF 25-75 outcomes at ’short’
time frame.
Outcome: 4 FEF 25-75 outcomes at ’short’ time frame
Mean Mean
Study or subgroup caffeine Control Difference Weight Difference
1 Low dose
Bukowskyj 1987 8 17 (11.33) 8 -6.33 (22) 59.5 % 23.33 [ 6.18, 40.48 ]
Subtotal (95% CI) 8 8 59.5 % 23.33 [ 6.18, 40.48 ]

2 High dose
Gong 1986 9 31.8 (23.6) 9 4 (21.3) 40.5 % 27.80 [ 7.03, 48.57 ]
Subtotal (95% CI) 9 9 40.5 % 27.80 [ 7.03, 48.57 ]

Total (95% CI) 17 17 100.0 % 25.14 [ 11.92, 38.37 ]
-50 -25 0 25 50

Analysis 1.5. Comparison 1 All caffeine doses versus placebo, Outcome 5 FEF 25-75 outcomes at ’medium’
time frame.
Outcome: 5 FEF 25-75 outcomes at ’medium’ time frame
Mean Mean
Study or subgroup caffeine Control Difference Weight Difference
1 Low dose
Bukowskyj 1987 8 25 (21.5) 8 -10.5 (18.5) 70.1 % 35.50 [ 15.85, 55.15 ]
Subtotal (95% CI) 8 8 70.1 % 35.50 [ 15.85, 55.15 ]

2 High dose
Gong 1986 9 33.1 (29.1) 9 6.9 (35.7) 29.9 % 26.20 [ -3.89, 56.29 ]
Subtotal (95% CI) 9 9 29.9 % 26.20 [ -3.89, 56.29 ]

Total (95% CI) 17 17 100.0 % 32.72 [ 16.26, 49.17 ]
-50 -25 0 25 50

Analysis 1.6. Comparison 1 All caffeine doses versus placebo, Outcome 6 FEF 25-75 outcomes at ’long’
time frame.
Outcome: 6 FEF 25-75 outcomes at ’long’ time frame
Mean Mean
1 Low dose
Bukowskyj 1987 8 9.5 (15.5) 8 -16.5 (26) 100.0 % 26.00 [ 5.02, 46.98 ]
Subtotal (95% CI) 8 8 100.0 % 26.00 [ 5.02, 46.98 ]

2 High dose
Total (95% CI) 8 8 100.0 % 26.00 [ 5.02, 46.98 ]
-50 -25 0 25 50

Analysis 1.7. Comparison 1 All caffeine doses versus placebo, Outcome 7 Gaw/VL outcomes at ’short’ time
frame.
Outcome: 7 Gaw/VL outcomes at ’short’ time frame
Mean Mean
1 Low dose
2 High dose
Gong 1986 9 37.8 (33.8) 9 7.5 (29.3) 100.0 % 30.30 [ 1.08, 59.52 ]
Subtotal (95% CI) 9 9 100.0 % 30.30 [ 1.08, 59.52 ]

Total (95% CI) 9 9 100.0 % 30.30 [ 1.08, 59.52 ]
-50 -25 0 25 50

Analysis 1.8. Comparison 1 All caffeine doses versus placebo, Outcome 8 FEV1 outcomes at 2 hours.
Outcome: 8 FEV1 outcomes at 2 hours
Std. Std.
Mean Mean
1 Low dose
Kivity 1990 10 3.48 (0.63) 10 3.23 (0.57) 100.0 % 0.40 [ -0.49, 1.29 ]
Subtotal (95% CI) 10 10 100.0 % 0.40 [ -0.49, 1.29 ]

2 High dose
Bukowskyj 1987 8 14 (19) 8 2 (14) 18.5 % 0.68 [ -0.34, 1.70 ]
Colacone 1990 10 0.1 (0.09) 10 0.05 (0.06) 23.5 % 0.63 [ -0.28, 1.53 ]
Crivelli 1986 7 1.71 (4.5) 7 -1.57 (3.21) 15.8 % 0.79 [ -0.32, 1.89 ]
Gong 1986 9 22.5 (13.5) 9 4 (18) 18.8 % 1.11 [ 0.10, 2.12 ]
Kivity 1990 10 3.61 (0.54) 10 3.23 (0.57) 23.4 % 0.66 [ -0.25, 1.56 ]
Subtotal (95% CI) 44 44 100.0 % 0.76 [ 0.32, 1.20 ]

-2 -1 0 1 2
Caffeine worse Caffeine better

Analysis 1.9. Comparison 1 All caffeine doses versus placebo, Outcome 9 FEV1 outcomes at 2 hours (High
dose).
Outcome: 9 FEV1 outcomes at 2 hours (High dose)
Mean Mean
Study or subgroup Mean Difference (SE) Difference Weight Difference
IV,Fixed,95% CI IV,Fixed,95% CI
1 % Change in FEV1
Bukowskyj 1987 12 (6) 11.8 % 12.00 [ 0.24, 23.76 ]
Crivelli 1986 3.29 (2.3) 80.6 % 3.29 [ -1.22, 7.80 ]
Gong 1986 18.5 (7.5) 7.6 % 18.50 [ 3.80, 33.20 ]
Subtotal (95% CI) 100.0 % 5.47 [ 1.43, 9.52 ]

Heterogeneity: Chi2 = 5.10, df = 2 (P = 0.08); I2 =61%
2 Post-treatment FEV1 litres
Kivity 1990 0.38 (0.19) 100.0 % 0.38 [ 0.01, 0.75 ]
Subtotal (95% CI) 100.0 % 0.38 [ 0.01, 0.75 ]

3 Change in FEV1 litres
Colacone 1990 0.05 (0.057) 100.0 % 0.05 [ -0.06, 0.16 ]
Subtotal (95% CI) 100.0 % 0.05 [ -0.06, 0.16 ]

-20 -10 0 10 20
Caffeine worse Caffeine better
ADDITIONAL TABLES
Table 1. Characteristics of studies used in meta-analysis
Study Dose of caffeine Formulation of dose Mean baseline Time of reading

% predicted FEV1 used in meta-analysis
Bukowskyj 1987 5 mg/kg Aqueous solution 48 2h
Colacone 1990 5 mg/kg Aqueous solution 84 2h
Crivelli 1986 6 mg/kg Aqueous solution -- 45 min

Table 1. Characteristics of studies used in meta-analysis (Continued)
Duffy 1991 5 mg/kg (’low’) Capsules 92.9 90 min

10 mg/kg (’high’)
Gong 1986 7.2 mg/kg Decaffeinated coffee 56 2h

plus caffeine
Kivity 1990 3.5 mg/kg (’low’) Capsules 78.8 2h

7 mg/kg (’high’)
Taylor 2004 15 g coffee Coffee of decaffeinated 94 --

coffee
APPENDICES
Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register
(CAGR)
Electronic searches: core databases
Database Frequency of search
MEDLINE (Ovid) Weekly
EMBASE (Ovid) Weekly
CENTRAL (The Cochrane Library) Quarterly
PSYCINFO (Ovid) Monthly
CINAHL (EBSCO) Monthly
AMED (EBSCO) Monthly
Handsearches: core respiratory conference abstracts

Conference Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI) 2001 onwards
American Thoracic Society (ATS) 2001 onwards
Asia Pacific Society of Respirology (APSR) 2004 onwards
British Thoracic Society Winter Meeting (BTS) 2000 onwards
Chest Meeting 2003 onwards
European Respiratory Society (ERS) 1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG) 2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ) 1999 onwards
MEDLINE search strategy used to identify trials for the CAGR
Asthma search
1. exp Asthma/
2. asthma$.mp.
3. (antiasthma$ or anti-asthma$).mp.
4. Respiratory Sounds/
5. wheez$.mp.
6. Bronchial Spasm/
7. bronchospas$.mp.
8. (bronch$ adj3 spasm$).mp.
9. bronchoconstrict$.mp.
10. exp Bronchoconstriction/
11. (bronch$ adj3 constrict$).mp.
12. Bronchial Hyperreactivity/
13. Respiratory Hypersensitivity/
14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.
15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.
16. or/1-15
Filter to identify RCTs

1. exp “clinical trial [publication type]”/
2. (randomised or randomised).ab,ti.
3. placebo.ab,ti.
4. dt.fs.
5. randomly.ab,ti.
6. trial.ab,ti.
7. groups.ab,ti.
8. or/1-7
9. Animals/
10. Humans/
11. 9 not (9 and 10)
12. 8 not 11
The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases
FEEDBACK
Historical use of caffeine
Summary
Reading the “Background” in the Abstract, it seems that the interest by caffeine as a bronchodilator is new. As a matter of fact, caffeine
is used for asthma since, at least, the last decades of 1800. We can find reference to this drug in Marcel Proust’s “A l’Ombre de Jeunes
Filles en Fleur”. This author, an asthmatic, refers that when he was very young (he was born in 1871) he used caffeine “that was
prescribed for help me breathing”.
Reply
Thank you for this comment.
Contributors
Roni Marques, chest physician.
WHAT’S NEW
Last assessed as up-to-date: 11 August 2011.
Date Event Description
15 June 2012 Review declared as stable This review is no longer being updated. The review remains of historic interest.
Because caffeine has a similar structure to other bronchodilators, trials have been
conducted to examine the effects on asthma monitoring. However, caffeine is not
a recognised treatment for asthma
15 June 2012 New search has been performed A literature search was conducted and one potentially eligible study was added
to ’studies awaiting classification’ but has not been fully incorporated in to the
review

HISTORY
Protocol first published: Issue 3, 1996
Review first published: Issue 2, 1998
Date Event Description
11 August 2011 New search has been performed New literature search run. No new eligible studies
identified. Minor copy edits made
29 September 2009 New citation required but conclusions have not New authorship of the review.
changed
27 August 2009 New search has been performed New search conducted, added new included study
(Taylor 2004), amendments made to Plain Language
Summary, reformatted Results and Discussion and
added ’Risk of bias’ and ’Summary of findings’ table.
Conclusions unchanged
21 July 2008 Amended Converted to new review format.
7 January 2005 New search has been performed New studies found and included or excluded: 8 Jan-
uary 2005
8 January 2003 New search has been performed New studies sought but none found: 8 January 2003
18 June 2001 New citation required and conclusions have changed Substantive amendment
CONTRIBUTIONS OF AUTHORS
Anna Bara and Elizabeth Barley extracted the data, did the meta-analyses and drafted the original review.
Emma Welsh updated the review, reformatted and redrafted it, added a new included study (Taylor 2004) and added ’Risk of bias’
tables. Chris Cates extracted data for the ’Risk of bias’ table, carried out the Generic Inverse Variance analyses and edited the review
update.
DECLARATIONS OF INTEREST
None known.

SOURCES OF SUPPORT
Internal sources
• NHS Research and Development, UK.
External sources
• No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

The 2009 update included regular caffeine-containing coffee versus decaffeinated coffee as a comparison type. The 2009 review also
compared lung function at all doses at two hours.
Serum caffeine levels was included as an outcome.
INDEX TERMS
Medical Subject Headings (MeSH)

∗ Respiratory Function Tests; Asthma [diagnosis; ∗ drug therapy]; Bronchi [drug effects]; Bronchodilator Agents [∗ pharmacology];
Caffeine [∗ pharmacology];Randomized Controlled Trials as Topic
MeSH check words

Adult; Humans


Welsh 2010

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Welsh 2010

Uploaded by

Copyright:

Available Formats

Caffeine for asthma (Review)

Welsh EJ, Bara A, Barley E, Cates CJ

Caffeine for asthma (Review)

Caffeine for asthma (Review) i

Caffeine for asthma

Emma J Welsh1 , Anna Bara2 , Elizabeth Barley3 , Christopher J Cates1

Editorial group: Cochrane Airways Group.

PLAIN LANGUAGE SUMMARY

The effect of caffeine in people with asthma

The general pharmacological effects of caffeine have been ex-

1. To identify all published randomised controlled trials of

1. Forced vital capacity (FVC)

Caffeine for asthma (Review) 3

Data collection and analysis

Caffeine for asthma (Review) 4

Caffeine for asthma (Review) 5

Caffeine for asthma (Review) 6

Caffeine for asthma (Review) 7

The papers differed in their reporting of serum caffeine levels.

Caffeine for asthma (Review) 8

Caffeine for asthma (Review) 9

Caffeine for asthma (Review) 10

Implications for research 6. Whether caffeine ingestion alters management decisions in

1. Patients’ perception of the effect of caffeine on their asthma

Kivity 1990 {published data only} References to studies awaiting assessment

Caffeine for asthma (Review) 12

Characteristics of included studies [ordered by study ID]

Methods Randomised controlled trial

Participants Ten patients admitted, 8 (4 male) completed the study

Interventions 5 mg/kg caffeine versus placebo as a solution in a juice drink

Notes Administration of corticosteroids was continued unchanged in those patients receiving

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No details

Allocation concealment (selection bias) Low risk Allocated by pharmacist

Blinding (performance bias and detection Low risk Quote: “Double-blinded”

Caffeine for asthma (Review) 13

when she developed dyspnoea.”

Methods Randomised controlled trial

Participants Ten adults (7 male) completed the study

Outcomes Change in FEV1, PC20

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No details

Allocation concealment (selection bias) Low risk Allocated by pharmacist

Incomplete outcome data (attrition bias) Low risk No dropouts

Caffeine for asthma (Review) 14

Methods Randomised controlled trial

Participants Seven adults (6 male) completed the study

Outcomes FEV1, SGaw

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No details

Allocation concealment (selection bias) Unclear risk Method of allocation unknown

Incomplete outcome data (attrition bias) Low risk No dropouts

Methods Randomised controlled trial

Participants 12 adults (11 male) admitted, 11 males completed the study

Exclusion criteria: upper respiratory tract infection or influenza vaccination within 6

Interventions 5 mg/kg, 10 mg/kg, placebo

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No details

Methods Randomised controlled trial. Method of allocation computer program

Participants Nine (4 male)

Caffeine for asthma (Review) 16

hepatic disease or hypertension

Bias Authors’ judgement Support for judgement